Cell-cell interactions guide development of the CNS, as is the case for all organ systems. The final form and organization of the CNS depends on these interactions between cells; these interactions are in turn dependent upon a number of specific classes of molecules, and foremost among them are the cell recognition molecules (CRMs). In the mature CNS, CRMs continue to be crucial for interactions between cells as in, for example, synapse formation, neurite extension, interactions between neurons and glia, cellular responses to injury, and many other cellular events. We are exploring the possibility that abnormalities in CRM functions are involved in neuropsychiatric disease, especially those disorders which may have a developmental component. Two particular molecules, N-CAM and L1 antigen, are abnormal in the cerebrospinal fluid of schizophrenic patients. The differences do not appear to represent a drug effect. Moreover, the abnormalities are present in a specific pattern, with the abnormality being seen in certain forms of each molecule: The 120 kD form of N-CAM is increased about two-fold in schizophrenic patients, while the 140 kD form of L1 antigen is decreased to a similar degree. Similarly, though smaller, changes in N-CAM are also seen in patients withbipolar mood disorder. Abnormalities in TGFs, which in some systems regulate expression of CRMs, do not appear to be responsible for these differences: TGFbeta2 was found to be increased in several degenerative disorders including Alzheimer's disease, Parkinson's disease, and multiple sclerosis, but not in schizophrenia. Animal studies suggest that expression of N-CAM and L1 is altered in brain areas that are deafferented by injury, and that exogenous L1 can promote plasticity of dopaminergic neurites. These data suggest a potential role of CRMs in neuropsychiatric disorders.